Although the link between hyperglycemia and microvascular complications (eg, neuropathy, nephropathy, and retinopathy) has been clearly demonstrated, less is known about the molecular mechanisms underlying this association. One potential mechanism under investigation is the protein kinase C (PKC) pathway. Under conditions of hyperglycemia, synthesis of diacylglycerol, a physiological activator of PKC, is increased. The PKC β2 isoform is activated in tissues that are usually affected by hyperglycemia (eg, retina, nerve, kidney, aorta, and heart). Specifically, PKC β activation is associated with a number of pathophysiologic changes seen in people with diabetic complications, including basement membrane thickening, leukocyte vascular adhesion, vascular permeability, and prolonged retinal circulation time. In animal models, the PKC β inhibitor ruboxistaurin (RBX) has been shown to positively affect a number of factors that contribute to diabetic retinopathy, including retinal circulation abnormalities, retinal vascular permeability, and intraocular neovascularization. RBX has also been shown to reduce the risk of visual loss among people with diabetes, an effect that was more pronounced among people with diabetic macular edema at baseline. The goals of this study were to evaluate the safety of repeated administration of RBX and to demonstrate the ability of RBX to exert a positive pharmacodynamic effect on the retinal microvasculature.
A total of 29 people participated in this double-masked, placebo-controlled, parallel, randomized single-center study. To be eligible for participation, the following criteria had to be met: diagnosis of type 1 or type 2 diabetes, age between 18 and 65 years, and Early Treatment of Diabetic Retinopathy Study retinopathy severity grade of ≤20 (ie, none or very mild nonproliferative diabetic retinopathy) in at least one eye. Exclusion criteria included: presence of other severe or chronically disabling conditions; presence of clinically significant macular edema; a history of intraocular surgery, laser photocoagulation or vitreous hemorrhage, uncontrolled diabetes (A1C >11%), impaired renal or hepatic function, anemia, or pregnancy or lactation. Participants who agreed to participate were randomized to receive placebo, 8 mg RBX BID, 16 mg RBX QD, or 16 mg RBX BID. RBX and placebo pills were identical, and participants were instructed to take pills with meals to maximize absorption. Treatment duration was 28 days. Primary endpoints included measures of safety and fluorescein angiographic assessment of mean retinal circulation time and retinal blood flow.
On average, participants were white (90%), middle aged (mean age = 41 years), overweight individuals (mean BMI = 30.7) with poor glycemic control (mean A1C = 8%), and had diabetes for an average of 5 years. The treatment groups did not differ on any of these factors at baseline. In terms of treatment-emergent adverse events, the only significant difference seen was an increase in abdominal pain in the placebo group (P = .049). There was a nonsignificant linear trend toward increased pain (all types) with increased doses of RBX, but no consistent pattern of pain was observed. Higher concentrations of serum uric acid were seen in the 16-mg–RBX–QD and the 16-mg–RBX–BID groups compared with the 8-mg–RBX–BID and placebo groups, although all mean serum uric acid concentrations were within the normal range. No significant differences in ocular safety parameters or immunology panel parameters were observed among the RBX and placebo groups. In terms of pharmacodynamic effects, retinal mean circulation time (RCT) was decreased by .68 seconds in the 16-mg–RBX–BID group, compared with an increase of .16 seconds in placebo-treated participants (P = .004). There was a significant dose-dependent effect of RBX on RCT (P = .027 for linear trend). A similar trend was observed for retinal blood flow, although that effect did not reach statistical significance.
In conclusion, RBX was well tolerated by patients with diabetes at doses up to 16 mg BID for a period of 28 days. RBX had significant ameliorative effects on retinal circulation time. This is the first study to demonstrate bioavailability of RBX to retinal vessels and a positive effect of RBX on RCT in humans.
